Novel 16alpha-ethynyl-19-nor-delta1, 3, 5(10)-androstatrienes



United States Patent 7 Claims. (cl. 167-65) The invention relates to novel l6a-ethynyl-l9-nor- A -androstatrienes of the formula wherein R is selected from the group consisting of hydrogen, lower alkyl having 1 to 7 carbon atoms and an acyl radical of an organic carboxylic acid having 1 to 8 carbon atoms and R is selected from the group consisting of hydrogen and an acyl radical of an organic carboxylic acid having 1 to 8 carbon atoms and to a process for their preparation. The organic carboxylic acids are such as alkanoic acids, alkenoic acids, cycloalkyl carboxylic acids, cycloalkyl alkanoic acids, arylalkanoic acids, aryl carboxylic acids, phenoxy alkanoic acids, heterocyclic carboxylic acids, fi-ketoalkanoic acids. The invention also relates to novel compositions having hypocholesterolemiant activity and to a novel method of treating hypercholesterolemia in warm-blooded animals.

Known steroid compounds proposed for the treatment of hypercholesterolemia, such as l7a-ethynyl-estradiol and 3-methyl-16a-chloro-estrone, have a low 'hypocholesterolemiant/estrogenic activity ratio and the activities cannot be separated. The compounds of Formula I, on the contrary, possess hypocholesterolemiant activity at doses without estrogenic activity. Thus the estrogenic activity of l6a-ethynyl-l9-nor-A -androstatrien 3,1618 diol is about 500 times weaker than that of l7a-ethynyl-estradiol.

It is an object of the invention to provide the novel l6a-ethynyl49-nor-A -androstatrienes of Formula I.

It is another object of the invention to provide a novel process for the preparation of the l6a-ethynyl-19-nor- A -androstatrienes of Formula I.

It is a further object of the invention to provide novel compositions possessing hypocholesterolemiant activity without estrogenic activity.

It is an additional object of the invention to provide a novel method of treating hypercholesterolemia in warmblooded animals.-

These and other objects and advantages of the invention will become obvious from the following detailed description.

The novel 16a-ethyny1-l9-nor-androstatrienes of the invention have the formula wherein R is selected from the group consisting of hydrogen, lower alkyl having 1 to 7 carbon atoms and an acyl radical of an organic carboxylic acid having to 1 to 8 3,282,786 Patented Nov. 1, 1966 carbon atoms and R is selected from the group consisting of hydrogen and an acyl radical of an organic carboxylic acid having 1 to 8 carbon atoms.

The process of the invention for the preparation of 16m ethynyl 19 nor-A -androstatriene-3,16/3-diol comprises reacting 19-nor-A -androstatriene-3-ol-16- one with an ethynyl ation agent, preferably acetylene in the presence of an alkali metal such as potassium in an organic solvent such as tert.-amyl alcohol, to form the said product which can then be converted into the corresponding ether or esters, if desired.

3-lower alkoxy-16a-ethynyl-19-nor-A -androstatriene-16B-ols can be formed by reacting l6a-ethynyl-19- nor-A -androstatriene-3,16,8-diol with a diazo lower alkane such as diazomethane or diazoethane or With a dilower alkyl sulfate such as dimethylsulfate or diethylsulfate in the presence of an alkaline base. The 16-esters of said 3-lower alkoxy compounds can be formed by reacting 3-lower alkoxy-lfiat-ethynyl-l9-nor-A -androstatriene-l6/3-ol with an acylating agent of an organic carboxylic acid having 1 to 8 carbon atoms such as acetic acid anhydride, propionic acid anhydride or benzoic acid anhydride in the presence of p-toluene-sulfonic acid.

3,165 diacyloxy 16a ethynyl-19-nor-A -androstatrienes can be formed by reacting 16a-ethynyl-19- nor-A -androstatriene-3,l6/8-di0l with an 'acylating agent of an organic carboxylic acid having 1 to 8 carbon atoms such as acetic acid anhydride, propionic acid anhydride or benzoic acid anhydride in the presence of ptoluene-sulfonic acid.

The novel compositions of the invention having hypocholesterolemiant activity are comprised of at least one -16a-ethynyl-19-nor-A -androstatriene of the formula 0R1 (Eon wherein R is selected from the group consisting of hydrogen, lower alkyl having 1 to 7 carbon atoms and an acyl radical of an organic carboxylic acid having 1 to 8 carbon atoms and R is selected from the group consisting of hydrogen and an acyl radical of an organic carboxylic acid having 1 to 8 carbon atoms and a major amount of a pharmaceutical carrier. The campositions may be prepared in the form of injectable solutions or suspensions,

RO- i in ampules and in multiple dose fiacons or in the form of tablets, coated tablets, glossettes, of capsules and of suppositories prepared in the usual manner.

The compositions can be used as a preventive or curative agent for the treatment of hypercholesterolemia in arterial disturbances, cerebral arteritis, aortitis, coronaritis, angina pectoris and atheromatosis.

The novel method of treating hypercholesterolemia in warm-blooded animals comprises administering daily an effective dose of a l6a-ethynyl-19-nor-A -androstatriene of the formula gen, lower alkyl having 1 to 7 carbon atoms and an acyl radical of an organic carboxylic acid having 1 to 8 carpended in an aqueous liquid dispersant was administered 'for a period of 10 days orally to groups of female rats having an average weight of about 200 gm. at daily dosages of from 0.5 to 2 and 5 mg./kg. of the said product. On the eleventh day, the animals were sacrificed and a sample of blood was taken from each animal and the seric sterols were determined. The surrenales, liver and kidneys were separated and weighed and a determination of the hepatic sterols were made for certain groups However, it 10 of rats. The following table gives the results obtained.

TABLE I Seric sterols Hepatic Liver Kidneys mg. Change of Lots Doses g./1,000 Sterols Surreuals mg. g. Percent g. Percent g. Weight,

g./1,000 Percent Control 0. 0.67"- 2- 56.0 4. 56 807 +10 Treated Animals mtg/kg 0.25 (63%) 2.31 (4%) 56.8 (+2%) 5 05 748 +9 Contro1 O 0.64..- 50. 4.17 749 +3 Treated Animals 2 mgJkg 0.46 (-23%).-. 53.9 (+6%). 4.16 774 l 0.5 mg./kg 0.62 (-3%) 53.9 (+6%)-- 4. 28 832 +2 should be understood that the invention is not intended to be limited to the specific embodiment.

EXAMPLE Preparation of 16a-ethynyl 19 nor A -andr0- statriene-3,16B-di0L-3 gm. of potassium were dissolved in 40 cc. of tertiary amyl alcohol at 100 C. under an atmosphere of nitrogen. The mixture was agitated for a period of 75 minutes and a stream of acetylene was then passed therethrough for a period of one hour. To 20 cc. of this solution, 1 gm. of 19-nor-A -androstatriene 3-ol-16-one was added under agitation at room temperature. A stream of acetylene was then passed therethrough for a period of three hours and after cc. of dilute acetic acid were added, the mixture was taken up with an equal volume of water.

The aqueous alcoholic phase was extracted with methylene chloride and the methylene chloride extract was washed with normal sulfuric acid, with water, and with a solution of sodium bicarbonate. Then, the organic phase was dried over magnesium sulfate and distilled to dryness under vacuum. The "residue obtained was dis-1 solved in 10 cc. of ethanol and 1 gm. of Girards reactant T and 1 cc. of acetic acid were added thereto. The mix ture was heated to reflux for one hour, cooled and poured into cc. of a normal solution of sodium hydroxide. The aqueous phase was extracted with methylene chloride andthe organic extract was dried over magnesium sulfate and distilled to dryness under vacuum. The residue was taken up in hot isopropyl ether which upon cooling gave a yield of 390 mg. of a product melting at 225 C.

This product was purified bysubjecting it to chromatography through alumina with elution with methylene .chlorideto obtain 190 mg. of 16m-ethynyl-19-nor-A androstatriene-3,16;3-diol in the form of a colorless, crystallized product. The said product was soluble in dilute .aqueous alkalis and chloroform, slightly soluble in ether and insoluble in water. The said product had a melting .point of 228-229 C. and had a specific rotation [a] =+106:t5 (c=0.25% dioxane). The chromatography of the mother liquors through alumina supplied a second yield of the said product.

. Ar 1 .alysis.-'C H O molecular weight=296.39. Calculated: C, 81.04%; H, 8.16%; O, 10.80%, Found: 80.9; 8.3; 10.6.

This product is not described in the literature.

The starting coupound, 19-nor=A -androstatri-t ene-301-16-one was obtained according to the process described by Hufiman et al. (J,.Am-.Chem. Soc., vol. 75, p. 4327 1953)). g

Pharmacological study of i6u-ethynyl-19-nor-A andr0statrz'ene-3,1 65-di0l p (A) Hyp'obholesterolemiant dctiv it y iri the female rat}- 16a-ethyny1-19-nor-A -androstadiene-3,l6 3-diol sus- Table I shows that 16a-ethynyl-19-nor-A -androstatriene-3,16,8-di0l possesses an important hypocholesterolemiant action at a dose of 5 mg./kg. when administered daily orally for a period of 10 days and that it does not modify the hepatic sterols. Also, it is quite active at a dose of 2 mg./kg. On the other hand, the product has no unfavorable influence on the growth of the animals nor on the weight of the surrenals, liver and kidneys. In addition, the appearance of desmosterol blood was not observed. Therefore, the product does not possess estrogenic activity at the doses at which it possesses hypocholesterolemiant activity.

Various modifications of the compositions and process may be made without departing from the spirit or scope thereof and it is to be understood that the invention is to be limited only as defined in the appended claims.

I claim: 1

1. A 16a-ethynyl-19-nor-A -androstatriene of the formula statriene of the formula I wherein R is selected from the group consisting of hydrogen, lower alkyl having 1 to 7 carbon atoms and an acyl radical of an organic carboxylic acid having 1 to 8 carbon atoms and R is selected from the group consisting of hydrogen and an acyl radical of an organic carboxylic acid having 1 to 8 carbon atoms and a major amount of a pharmaceutical carrier.

4. The composition of claim 3 wherein the said 16aethynyl-19-nor-A -androstatriene is 16a-ethynyl-l9- nor-M -androstatriene-3,l6fi-diol.

5. A method of treating hypercholesterolemia in warmblooded animals which comprises administering daily to the animals an eifective amount of a 16a-ethynyl-19-nor- A andr0statriene of the formula wherein R is selected from the group consisting of hydrogen, lower alkyl having 1 to 7 carbon atoms and an acyl References Cited by the Examiner UNITED STATES PATENTS 7/1958 Colton 260397.5 9/1958 Hoehn et a1, 260397.4

LEWIS GOTTS, Primary Examiner.

ELBERT L. ROBERTS, Examiner.

radical of an organic carboxylic acid having 1 to 8 20 HENRY FRENCH, Assistant Examiner- 

5. A METHOD OF TREATING HYPERCHOLESTEROLEMIA IN WARMBLOODED ANIMALS WHICH COMPRISES ADMINISTERING DAILY TO THE ANIMALS AN EFFECTIVE AMOUNT OF A 16A-ETHYNYL-19-NOR $1,3,5,(10)-ANDROSTATRIENE OF THE FORMULA 